tbuckley/cabot-search huggingface dataset:
T cell-mediated additive cytotoxicity – death by multiple bullets
Authors: Bettina Weigelin, Peter Friedl
Journal: Trends in cancer (2022)

Immune effector cells, including cytotoxic T cells (CTLs), induce apoptosis and eliminate target cells by direct cell-cell contacts. In vivo, CTLs fail to efficiently kill solid tumor cells by individual contacts but rely upon multihit interactions by many CTLs (swarming). Recent evidence has indicated that multihit interactions by CTLs induce a series of sublethal damage events in target cells, including perforin-mediated membrane damage, induction of reactive oxygen species (ROS), nuclear envelope rupture, and DNA damage. Individual damage can be repaired, but when induced in rapid sequence, sublethal damage can accumulate and induce target cell death. Here, we summarize the sublethal damage and additive cytotoxicity concepts for CTL-induced and other cell stresses and discuss the implications for improving immunotherapy and multitargeted anticancer therapies.
Emerging novel sub-lineage BA.2.75: The next dominant omicron variant?
Authors: Ranjan K. Mohapatra, Venkataramana Kandi, Snehasish Mishra, Ashish K. Sarangi, Manoj Kumar Pradhan, Pranab K. Mohapatra, Ajit Behera, Kuldeep Dhama
Journal: International Journal of Surgery (2022)
Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling
Authors: Zhonglou Sun, Helong Zhao, Daniel Fang, Chadwick T. Davis, Dallas S. Shi, Kachon Lei, Bianca E. Rich, Jacob M. Winter, Li Guo, Lise K. Sorensen, Robert J. Pryor, Nina Zhu, Samuel Lu, Laura L. Dickey, Daniel J. Doty, Zongzhong Tong, Kirk R. Thomas, Alan L. Mueller, Allie H. Grossmann, Baowei Zhang, Thomas E. Lane, Robert S. Fujinami, Shannon J. Odelberg, Weiquan Zhu
Journal: Neuron (2022)

Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1β-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway. Inhibiting the activation of ARF6 both prevents and reverses EndoMT, stabilizes BCNSB function, reduces demyelination, and attenuates symptoms even after the establishment of severe EAE, without immunocompromising the host. Pan-inhibition of ALKs also reduces disease severity in the EAE model. Therefore, multiple components of the IL-1β-ARF6-ALK-SMAD1/5 pathway could be targeted for the treatment of a variety of neuroinflammatory disorders.
Dose–response association of aerobic and muscle-strengthening physical activity with mortality: a national cohort study of 416 420 US adults
Authors: Carver J Coleman, Daniel J McDonough, Zachary C Pope, C Arden Pope
Journal: British Journal of Sports Medicine (2022)

Objectives To investigate the dose–response association of aerobic physical activity (PA) and muscle-strengthening exercise (MSE) with all-cause mortality. Methods National Health Interview Survey data (1997–2014) were linked to the National Death Index through 2015, which produced a cohort of 416 420 US adults. Cox proportional-hazard models were used to estimate HRs and 95% CIs for the associations of moderate aerobic PA (MPA), vigorous aerobic PA (VPA) and MSE with mortality risk. Models controlled for age, sex, race-ethnicity, income, education, marital status, survey year, smoking status, body mass index and chronic conditions. Results Relative to those who engaged in no aerobic PA, substantial mortality risk reduction was associated with 1 hour/week of aerobic PA (HR: 0.85, 95% CI: 0.83 to 0.86) and levelled off at 3 hours/week of aerobic PA (0.73, 0.71 to 0.75). Similar results were observed for men and women and for individuals younger and older than 60 years. MSE conferred additional mortality risk reduction at 1 time/week (0.89, 0.81 to 0.97) and appeared no longer beneficial at 7 times/week (0.99, 0.94 to 1.04). Conclusion The minimum effective dose of aerobic PA for significant mortality risk reduction was 1 hour/week of MPA or VPA, with additional mortality risk reduction observed up to 3 hours/week. For older adults, only small decreases in mortality risk were observed beyond this duration. Completing MSE in combination with aerobic PA conferred additional mortality risk reduction, with a minimum effective dose of 1–2 times/week.
Diagnosis of acute appendicitis
Authors: L. Devey
Journal: BMJ (2001)

Doctors must learn to let others treat them and their familiesEditor-My parents, who are 92 and 86 and otherwise in excellent health, are both virtually blind as a result of glaucoma detected too late.It is not their having the condition that saddens me, as they still manage to maintain their independence and constantly push the boundaries of their impairment in order to enjoy life to the full.What is sad is that neither of them can attribute late diagnosis and the attendant complications to social deprivation, poor access to medical care, or any of the factors identified by Fraser et al. 1 Quite the opposite, in fact.My father is a retired general practitioner, a prominent member of the community in which I grew up.The best ophthalmologists in town would have readily investigated and treated him or any of his immediate family free of charge-if they had been asked to do so.The problem is that too many doctors still tend to treat themselves and their families rather than delegate this important responsibility to colleagues.In doing so, they sacrifice objectivity and sentence themselves and their families to a lifetime of well meant, but severely compromised, medical care.My father was no exception.How many doctors are able to separate their personal and professional responsibilities and enter themselves and their families into appropriate health surveillance programmes, so that conditions such as glaucoma are not missed?The alternativeseeing your children die of diseases associated with social deprivation and poor access to medical care-is sobering.
Embracing the monsters: moving from infection control to microbial management
Authors: Claas Kirchhelle, Adam P Roberts
Journal: The Lancet Microbe (2022)

"The old world is dying, and the new world struggles to be born: now is the time of monsters."1 Slovenian philosopher Slavoy Žižek's loose translation of Prison Notebooks—a series of essays written by Italian communist leader Antonio Gramsci—rings eerily familiar in 2022. Around the world, societies are facing intense pressure due to the accelerating climate emergency and the environmental monsters it is unleashing, which range from rising oceans and scorching heatwaves to a rapidly accelerating cycle of emerging and re-emerging diseases.
A clinical decision support system optimising adjuvant chemotherapy for colorectal cancers by integrating deep learning and pathological staging markers: a development and validation study
Authors: Andreas Kleppe, Ole-Johan Skrede, Sepp De Raedt, Tarjei S Hveem, Hanne A Askautrud, Jørn E Jacobsen, David N Church, Arild Nesbakken, Neil A Shepherd, Marco Novelli, Rachel Kerr, Knut Liestøl, David J Kerr, Håvard E Danielsen
Journal: The Lancet Oncology (2022)
Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial
Authors: Virginie Westeel, Pascal Foucher, Arnaud Scherpereel, Jean Domas, Philippe Girard, Jean Trédaniel, Marie Wislez, Patrick Dumont, Elisabeth Quoix, Olivier Raffy, Denis Braun, Marc Derollez, François Goupil, Jacques Hermann, Etienne Devin, Hubert Barbieux, Eric Pichon, Didier Debieuvre, Gervais Ozenne, Jean-François Muir, Stéphanie Dehette, Jérôme Virally, Michel Grivaux, François Lebargy, Pierre-Jean Souquet, Faraj Al Freijat, Nicolas Girard, Emmanuel Courau, Reza Azarian, Michel Farny, Jean-Paul Duhamel, Alexandra Langlais, Franck Morin, Bernard Milleron, Gérard Zalcman, Fabrice Barlesi
Journal: The Lancet Oncology (2022)
An antibody from single human V <sub>H</sub> -rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion
Authors: Sai Luo, Jun Zhang, Alex J. B. Kreutzberger, Amanda Eaton, Robert J. Edwards, Changbin Jing, Hai-Qiang Dai, Gregory D. Sempowski, Kenneth Cronin, Robert Parks, Adam Yongxin Ye, Katayoun Mansouri, Maggie Barr, Novalia Pishesha, Aimee Chapdelaine Williams, Lucas Vieira Francisco, Anand Saminathan, Hanqin Peng, Himanshu Batra, Lorenza Bellusci, Surender Khurana, S. Munir Alam, David C. Montefiori, Kevin O. Saunders, Ming Tian, Hidde Ploegh, Tom Kirchhausen, Bing Chen, Barton F. Haynes, Frederick W. Alt
Journal: Science Immunology (2022)

SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human V H 1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several V H 1-2/Vκ1-33–based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient–derived V H 1-2–based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy–based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.
The Modular µSiM Reconfigured: Integration of Microfluidic Capabilities to Study In Vitro Barrier Tissue Models under Flow
Authors: Mehran Mansouri, Adeel Ahmed, S. Danial Ahmad, Molly C. McCloskey, Indranil M. Joshi, Thomas R. Gaborski, Richard E. Waugh, James L. McGrath, Steven W. Day, Vinay V. Abhyankar
Journal: Advanced Healthcare Materials (2022)

Microfluidic tissue barrier models have emerged to address the lack of physiological fluid flow in conventional "open-well" Transwell-like devices. However, microfluidic techniques have not achieved widespread usage in bioscience laboratories because they are not fully compatible with traditional experimental protocols. To advance barrier tissue research, there is a need for a platform that combines the key advantages of both conventional open-well and microfluidic systems. Here, a plug-and-play flow module is developed to introduce on-demand microfluidic flow capabilities to an open-well device that features a nanoporous membrane and live-cell imaging capabilities. The magnetic latching assembly of this design enables bi-directional reconfiguration and allows users to conduct an experiment in an open-well format with established protocols and then add or remove microfluidic capabilities as desired. This work also provides an experimentally-validated flow model to select flow conditions based on the experimental needs. As a proof-of-concept, flow-induced alignment of endothelial cells and the expression of shear-sensitive gene targets are demonstrated, and the different phases of neutrophil transmigration across a chemically stimulated endothelial monolayer under flow conditions are visualized. With these experimental capabilities, it is anticipated that both engineering and bioscience laboratories will adopt this reconfigurable design due to the compatibility with standard open-well protocols.
Management of<i>Helicobacter pylori</i>infection: the Maastricht VI/Florence consensus report
Authors: Peter Malfertheiner, Francis Megraud, Theodore Rokkas, Javier P Gisbert, Jyh-Ming Liou, Christian Schulz, Antonio Gasbarrini, Richard H Hunt, Marcis Leja, Colm O'Morain, Massimo Rugge, Sebastian Suerbaum, Herbert Tilg, Kentaro Sugano, Emad M El-Omar
Journal: Gut (2022)

Helicobacter pylori Infection is formally recognised as an infectious disease, an entity that is now included in the International Classification of Diseases 11th Revision. This in principle leads to the recommendation that all infected patients should receive treatment. In the context of the wide clinical spectrum associated with Helicobacter pylori gastritis, specific issues persist and require regular updates for optimised management. The identification of distinct clinical scenarios, proper testing and adoption of effective strategies for prevention of gastric cancer and other complications are addressed. H. pylori treatment is challenged by the continuously rising antibiotic resistance and demands for susceptibility testing with consideration of novel molecular technologies and careful selection of first line and rescue therapies. The role of H. pylori and antibiotic therapies and their impact on the gut microbiota are also considered. Progress made in the management of H. pylori infection is covered in the present sixth edition of the Maastricht/Florence 2021 Consensus Report, key aspects related to the clinical role of H. pylori infection were re-evaluated and updated. Forty-one experts from 29 countries representing a global community, examined the new data related to H. pylori infection in five working groups: (1) indications/associations, (2) diagnosis, (3) treatment, (4) prevention/gastric cancer and (5) H. pylori and the gut microbiota. The results of the individual working groups were presented for a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in various clinical fields.
Publisher Correction: A T cell resilience model associated with response to immunotherapy in multiple tumor types
Authors: Yu Zhang, Trang Vu, Douglas C. Palmer, Rigel J. Kishton, Lanqi Gong, Jiao Huang, Thanh Nguyen, Zuojia Chen, Cari Smith, Ferenc Livák, Rohit Paul, Chi-Ping Day, Chuan Wu, Glenn Merlino, Kenneth Aldape, Xin-yuan Guan, Peng Jiang
Journal: Nature Medicine (2022)
Diagnosis, Treatment, and Prevention of Pulmonary Embolism
Authors: Samuel Z. Goldhaber
Journal: JAMA (1992)

To assess the state of the art of venous thrombosis and pulmonary embolism for the medical and other health-related professions, the World Health Organization (WHO) and the International Society and Federation of Cardiology (ISFC) convened a task force in Geneva, Switzerland. Members of the task force prepared position papers and presented brief oral presentations. A report was subsequently prepared by the task force members, who contributed sections in their areas of expertise. Revisions of the report occurred both during the task force meeting itself in Geneva and during the ensuing months. The final report was approved by the WHO-ISFC Task Force on Pulmonary Embolism Steering Committee. More quantitative information is needed on the frequency of venous thrombosis and pulmonary embolism in hospitalized medical patients as well as in outpatients at high risk. Population studies should focus on incidence, survival, and long-term complications in different parts of the world with respect to gender and race. Further educational efforts are needed to increase awareness about venous thrombosis and pulmonary embolism prophylaxis. Finally, research into effective techniques for changing physician practice would be useful. (<i>JAMA</i>. 1992;268:1727-1733)
Minimal invasiveness in soft tissue augmentation at dental implants: A systematic review and meta‐analysis of patient‐reported outcome measures
Authors: Daniel S. Thoma, Franz J. Strauss, Leonardo Mancini, Thomas J. W. Gasser, Ronald E. Jung
Journal: Periodontology 2000 (2022)

Abstract The aim of this study was to compare patient‐reported outcome measures (PROMs) of soft tissue substitutes versus autogenous grafts for soft tissue augmentation procedures at implant sites. Comprehensive and systematic literature searches were performed until December 2021. A focused question was formulated based on the Population, Intervention, Comparison and Outcome criteria (PICO): In patients with dental implants undergoing soft tissue augmentation (P), do soft tissue substitutes (I) compared to autogenous soft tissue graft (SCTG [subepithelial connective tissue graft]) (C) limit the post‐operative morbidity and other patient reported‐outcomes measures (O). Randomized controlled clinical trials, prospective‐, retrospective‐ and case‐series studies were included. Meta‐analyses were performed whenever possible and the results were expressed as weighted mean differences (WMD). A total of 29 clinical studies were included. For mucosal thickness gain, soft tissue substitutes significantly reduced the pain perception compared to SCTG (n = 4; WMD = 14.91 Visual Analog Scale [VAS] units; 95% confidence interval [CI] 6.42‐23.40; P &lt; .0006) based on a 0‐100 VAS scale. Based on a 0‐10 VAS scale, a borderline significance of pain reduction was found when soft tissue substitutes were applied (n = 4; WMD = 1.62 VAS units; 95% CI 0.01‐3.23; P = .05). For keratinized tissue gain, soft tissue substitutes significantly reduced the pain perception after keratinized tissue augmentation compared to SCTG based on a 0‐100 VAS scale (n = 2; WMD = 21.43 VAS units; 95% CI 12.58‐30.28; P &lt; .0001). Based on the 0‐10 VAS scale, soft tissue substitutes significantly reduced the pain as compared to SCTG (n = 4; WMD = 1.65 VAS units; 95% CI 0.66‐2.64; P = .001). Regarding pain medication, soft tissue substitutes required less painkillers (n = 6; WMD = 1.56 tablets; 95% CI 1.22‐1.91; P &lt; .00001) after soft tissue augmentation. The surgery time was significantly reduced when soft tissue substitutes were used (n = 5; WMD = 10.9 minutes; 95% CI 4.60‐17.19; P &lt; .00001). There were no significant differences in satisfaction, aesthetics, and quality of life (OHIP‐14) between soft tissue substitutes and autogenous grafts following soft tissue augmentation at implants sites. Soft tissue substitutes, compared to autogenous grafts, significantly improve PROMs following soft tissue augmentation at implant sites. Soft tissue substitutes can reduce pain perception, amounts of painkillers and surgery time while achieving similar levels of patient´s satisfaction as autogenous grafts without impairing the clinical outcomes. The current evidence indicates that they constitute a valid and reliable alternative to minimize the invasiveness in soft tissue augmentation procedures at implant sites.
Mesenchymal stromal cells-derived extracellular vesicles reprogramme macrophages in ARDS models through the miR-181a-5p-PTEN-pSTAT5-SOCS1 axis
Authors: Yue Su, Johnatas Dutra Silva, Declan Doherty, David A Simpson, Daniel J Weiss, Sara Rolandsson-Enes, Daniel F McAuley, Cecilia M O'Kane, Derek P Brazil, Anna D Krasnodembskaya
Journal: Thorax (2022)

Rationale A better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming. Methods Human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and hyper-inflammatory phenotype) and treated with MSC conditioned medium (CM) or EVs. Protein expression was measured by Western blot. EV micro RNA (miRNA) content was determined by miRNA sequencing. In vivo: LPS-injured C57BL/6 mice were given EVs isolated from MSCs in which miR-181a had been silenced by miRNA inhibitor or overexpressed using miRNA mimic. Results EVs were the key component of MSC CM responsible for anti-inflammatory modulation of human macrophages. EVs significantly reduced secretion of tumour necrosis factor-α and interleukin-8 by LPS-stimulated or ARDS plasma-stimulated MDMs and this was dependent on SOCS1. Transfer of miR-181a in EVs downregulated phosphatase and tensin homolog (PTEN) and subsequently activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) leading to upregulation of SOCS1 in macrophages. In vivo, EVs alleviated lung injury and upregulated pSTAT5 and SOCS1 expression in alveolar macrophages in a miR181-dependent manner. Overexpression of miR-181a in MSCs significantly enhanced therapeutic efficacy of EVs in this model. Conclusion miR-181a-PTEN-pSTAT5-SOCS1 axis is a novel pathway responsible for immunomodulatory effect of MSC EVs in ARDS.
History of Adrenal Research: From Ancient Anatomy to Contemporary Molecular Biology
Authors: Walter L Miller, Perrin C White
Journal: Endocrine Reviews (2022)

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.
Metastasis
Authors: David Lyden, Cyrus M. Ghajar, Ana Luísa Correia, Julio A. Aguirre-Ghiso, Shang Cai, Maria Rescigno, Peiyuan Zhang, Guohong Hu, Sarah-Maria Fendt, Adrienne Boire, Ralph R. Weichselbaum, Rohan R. Katipally
Journal: Cancer Cell (2022)
Personalized pre-habilitation reduces anastomotic complications compared to up front surgery before ileocolic resection in high-risk patients with Crohn's disease: A single center retrospective study
Authors: Charlotte Ferrandis, Regis Souche, Thomas Bardol, Lucile Boivineau, Jean-Michel Fabre, Romain Altwegg, Francoise Guillon
Journal: International Journal of Surgery (2022)